This application is for the Continuation of the Case Western Reserve University (CWRU) Clinical Site and its Subsites of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Nonalcoholic fatty liver disease (NAFLD) affects nearly a third of adults and a fifth of children in North America and is a major public health issue in the United States. NAFLD, and especially nonalcoholic steatohepatitis (NASH), lead to end-stage liver disease and primary liver cancer, as well as liver-, cardiovascular-, and cancer-related mortality, resulting in major increases in health burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the growing public health burden of NASH that can only be addressed through this large research consortium with a demonstrated track record of success in previous cycles. The primary objective of the NASH CRN is to perform clinical research on NASH and NAFLD in adults and children. Another high priority objective is to conduct translational research in NASH and NAFLD focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, treatment, and clinical management. In the next phase of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycle will be completed, and new therapeutic trials, including phase 2a proof of mechanism and phase 2b clinical trials will be initiated, to develop evidence-based treatment options that are safe, effective, simple, and inexpensive. The longitudinal cohort of adults and children with NAFLD will be extended, which will prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation, and development and validation of non-invasive techniques to evaluate and identify those with NASH/NAFLD, who will respond, and how quickly the disease is progressing. CWRU has played a leading role in both the clinical and translational research success of the NASH CRN since the inception. CWRU was a leading enrolling site in both the PIVENS and FLINT trials. CWRU investigators are uniquely placed in improving understanding of systemic abnormalities including cardiovascular and skeletal muscle dysfunction in NAFLD. The role of sarcopenia and myostatin, a TGF? superfamily member, as a therapeutic target in NASH is a paradigm shifting approach to novel targets for the nearly ubiquitous disease. Given the high recruitment, retention and quality of data from CWRU, and our continued commitment to the success of the collaboration, the NASH CRN is poised to continue its major impact on the field and directly advance the mission of the NIH to improve the health of the public.